Synthetic methods for spiro-oxindole compounds

ABSTRACT

This invention is directed to methods of preparing certain spiro-oxindole derivatives, which are useful for the treatment and/or prevention of sodium channel-mediated diseases or conditions, such as pain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/272,297, filed May 7, 2014 (now allowed); which is a continuation ofU.S. patent application Ser. No. 13/620,391, filed Sep. 14, 2012 (nowU.S. Pat. No. 8,742,109); which is a divisional application of U.S.patent application Ser. No. 12/904,880, filed Oct. 14, 2010 (now U.S.Pat. No. 8,445,696); all of which claim the benefit under 35 U.S.C.§119(e) of U.S. Provisional Patent Application No. 61/251,335, filedOct. 14, 2009. These applications are incorporated herein by referencein their entirety.

FIELD OF THE INVENTION

The present invention is directed to improved methods of preparingcertain spiro-oxindole compounds as well as various intermediatesinvolved therein. In particular, this invention is directed to methodsof preparing spiro-oxindole compounds, and their pharmaceuticallyacceptable salts, which are useful in treating sodium channel-mediateddiseases or conditions, such as pain, as well as other diseases andconditions associated with the mediation of sodium channels.

BACKGROUND OF THE INVENTION

Sodium channels play a diverse set of roles in maintaining normal andpathological states, including the long recognized role that voltagegated sodium channels play in the generation of abnormal neuronalactivity and neuropathic or pathological pain. Damage to peripheralnerves following trauma or disease can result in changes to sodiumchannel activity and the development of abnormal afferent activityincluding ectopic discharges from axotomised afferents and spontaneousactivity of sensitized intact nociceptors. These changes can producelong-lasting abnormal hypersensitivity to normally innocuous stimuli, orallodynia. Examples of neuropathic pain include, but are not limited to,post-herpetic neuralgia, trigeminal neuralgia, diabetic neuropathy,chronic lower back pain, phantom limb pain, and pain resulting fromcancer and chemotherapy, chronic pelvic pain, complex regional painsyndrome and related neuralgias.

There have been some advances in treating neuropathic pain symptoms byusing medications, such as gabapentin, and more recently pregabalin, asshort-term, first-line treatments. However, pharmacotherapy forneuropathic pain has generally had limited success with little responseto commonly used pain reducing drugs, such as NSAIDS and opiates.Consequently, there is still a considerable need to explore noveltreatment modalities.

There remain a limited number of potent effective sodium channelblockers with a minimum of adverse events in the clinic. There is alsoan unmet medical need to treat neuropathic pain and other sodium channelassociated pathological states effectively and without adverse sideeffects.

PCT Published Patent Application No. WO 2006/110917, PCT PublishedPatent Application No. WO 2010/45251 and PCT Patent Application No.PCT/US2010/040187 discloses certain spiro-oxindole compounds. Thesecompounds are disclosed therein as being useful for the treatment ofsodium channel-mediated diseases, preferably diseases related to pain,central nervous conditions such as epilepsy, anxiety, depression andbipolar disease; cardiovascular conditions such as arrhythmias, atrialfibrillation and ventricular fibrillation; neuromuscular conditions suchas restless leg syndrome; neuroprotection against stroke, neural traumaand multiple sclerosis; and channelopathies such as erythromelalgia andfamilial rectal pain syndrome.

Methods of preparing these compounds and pharmaceutical compositionscontaining them are also disclosed in PCT Published Patent ApplicationNo. WO 2006/110917, PCT Published Patent Application No. WO 2010/45251and PCT Patent Application No. PCT/US2010/040187.

There exists, therefore, a need for improved methods of preparingcertain spiro-oxindole compounds.

SUMMARY OF THE INVENTION

The present invention is directed to methods of preparing certainspiro-oxindole compounds as single stereoisomers or single enantiomers,or mixtures thereof, or as pharmaceutically acceptable salts thereof.These compounds are useful in treating sodium channel-mediated diseasesand conditions, such as pain.

Accordingly, in one aspect, this invention is directed to a method ofpreparing a compound of formula (I):

or a pharmaceutically acceptable salt thereof, as a single stereoisomeror enantiomer or a mixture thereof;

-   wherein the method comprises treating a compound of formula (8):

or a pharmaceutically acceptable salt thereof, with a compound offormula (9):

or a pharmaceutically acceptable salt thereof, under suitable conditionsto provide the compound of formula (I), or a pharmaceutically acceptablesalt thereof, as a single stereoisomer or enantiomer or a mixturethereof.

In another aspect, this invention is directed to a method of preparing acompound of formula (I-S):

or a pharmaceutically acceptable salt thereof, and a compound of formula(I-R):

or a pharmaceutically acceptable salt thereof, wherein the methodcomprises resolving a compound of formula (I):

or a pharmaceutically acceptable salt thereof, as a single stereoisomeror enantiomer or a mixture thereof; under suitable conditions to yield acompound of formula (I-S), or a pharmaceutically acceptable saltthereof, and a compound of formula (I-R), or a pharmaceuticallyacceptable salt thereof.

In another aspect, this invention is directed to a method of preparing acompound of formula (II):

or a pharmaceutically acceptable salt thereof, as a single stereoisomeror enantiomer or a mixture thereof;

-   wherein the method comprises treating a compound of formula (15):

or a pharmaceutically acceptable salt thereof, with a compound offormula (16):

or a pharmaceutically acceptable salt thereof, under suitable conditionsto provide the compound of formula (II), or a pharmaceuticallyacceptable salt thereof, as a single stereoisomer or enantiomer or amixture thereof.

In another aspect, this invention is directed to a method of preparing acompound of formula (II-S):

or a pharmaceutically acceptable salt thereof, and a compound of formula(II-R):

or a pharmaceutically acceptable salt thereof, wherein the methodcomprises resolving a compound of formula (II):

or a pharmaceutically acceptable salt thereof, as a single stereoisomeror enantiomer or a mixture thereof; under suitable conditions to yield acompound of formula (II-S), or a pharmaceutically acceptable saltthereof, and a compound of formula (II-R), or a pharmaceuticallyacceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

“Amino” refers to the —NH₂ substituent.

“Cyano” refers to the —CN substituent.

“Hydroxyl” refers to the —OH substituent.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ substituent.

“Oxo” refers to the ═O substituent.

“Trifluoromethyl” refers to the —CF₃ substituent.

“Analgesia” refers to an absence of pain in response to a stimulus thatwould normally be painful.

“Allodynia” refers to a condition in which a normally innocuoussensation, such as pressure or light touch, is perceived as beingextremely painful.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets, (e.g., cats, dogs, swine, cattle, sheep,goats, horses, and rabbits), and non-domestic animals such as wildelifeand the like.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

(i) preventing the disease or condition from occurring in a mammal, inparticular, when such mammal is predisposed to the condition but has notyet been diagnosed as having it;

(ii) inhibiting the disease or condition, i.e., arresting itsdevelopment;

(iii) relieving the disease or condition, i.e., causing regression ofthe disease or condition; or

(iv) relieving the symptoms resulting from the disease or condition,i.e., relieving pain without addressing the underlying disease orcondition.

As used herein, the terms “disease” and “condition” may be usedinterchangeably or may be different in that the particular malady orcondition may not have a known causative agent (so that etiology has notyet been worked out) and it is therefore not yet recognized as a diseasebut only as an undesirable condition or syndrome, wherein a more or lessspecific set of symptoms have been identified by clinicians.

The compounds prepared herein may contain one or more asymmetric centresand may thus give rise to enantiomers that may be defined, in terms ofabsolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for aminoacids. The present invention is meant to include all such possibleenantiomers, as well as their racemic and optically pure forms.Optically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers maybe prepared using chiral synthons or chiral reagents, or resolved usingconventional techniques, for example, chromatography and fractionalcrystallisation, or by the techniques disclosed herein. Conventionaltechniques for the preparation/isolation of individual enantiomersinclude chiral synthesis from a suitable optically pure precursor orresolution of the racemate (or the racemate of a salt or derivative)using, for example, chiral high pressure liquid chromatography (HPLC).

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system, using the ACD/NameVersion 9.07 software program, wherein the compounds of the inventionare named herein as derivatives of the central core structure, i.e., the2-oxindole structure. For complex chemical names employed herein, asubstituent group is named before the group to which it attaches. Forexample, cyclopropylethyl comprises an ethyl backbone with cyclopropylsubstituent. In chemical structure diagrams, all bonds are identified,except for some carbon atoms, which are assumed to be bonded tosufficient hydrogen atoms to complete the valency.

Thus, for example, a compound of formula (I):

is named herein as1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one.

Embodiments of the Invention

Of the various aspects of the invention set forth above in the Summaryof the Invention, certain embodiments of the methods disclosed hereinare preferred.

Of the method of preparing a compound of formula (I), as set forth abovein the Summary of the Invention, or a pharmaceutically acceptable saltthereof, as a single stereoisomer or enantiomer or a mixture thereof,one embodiment is the method which further comprises the preparation ofa compound of formula (8), or a pharmaceutically acceptable saltthereof, wherein a compound of formula (7):

or a pharmaceutically acceptable salt thereof, is treated with a baseunder suitable conditions to form the compound of formula (8), or apharmaceutically acceptable salt thereof.

Of this embodiment, another embodiment is a method which furthercomprises the preparation of the compound of formula (7), or apharmaceutically acceptable salt thereof, wherein a compound of formula(6):

or a pharmaceutically acceptable salt thereof, is treated under standardMitsunobu reaction conditions to form a compound of formula (5), or apharmaceutically acceptable salt thereof.

Of this embodiment, another embodiment is a method which furthercomprises the preparation of the compound of formula (6), or apharmaceutically acceptable salt thereof, wherein a compound of formula(5):

or a pharmaceutically acceptable salt thereof, is treated with analdehyde under suitable conditions to form the compound of formula (6),or a pharmaceutically acceptable salt thereof.

Of this embodiment, another embodiment is a method which furthercomprises the preparation of the compound of formula (5), or apharmaceutically acceptable salt thereof, wherein a compound of formula(4):

or a pharmaceutically acceptable salt thereof, is treated under suitableconditions to form the compound of formula (5), or a pharmaceuticallyacceptable salt thereof.

Of this embodiment, another embodiment is a method which furthercomprises the preparation of the compound of formula (4), or apharmaceutically acceptable salt thereof, wherein a compound of formula(2):

or a pharmaceutically acceptable salt thereof, is treated with aGrignard reagent of formula (3):

under suitable conditions to form an intermediate product; and theintermediate product is then reacted with a compound of formula (1):

or a pharmaceutically acceptable salt thereof, under suitable conditionsto form the compound of formula (4), or a pharmaceutically acceptablesalt thereof.

Of the method of preparing a compound of formula (II), as set forthabove in the Summary of the Invention, or a pharmaceutically acceptablesalt thereof, as a single stereoisomer or enantiomer or a mixturethereof, one embodiment is the method which further comprises thepreparation of a compound of formula (15), or a pharmaceuticallyacceptable salt thereof, wherein a compound of formula (14):

or a pharmaceutically acceptable salt thereof, is treated with analkylating agent under suitable conditions to form the compound offormula (15), or a pharmaceutically acceptable salt thereof.

Of this embodiment, another embodiment is a method which furthercomprises the preparation of the compound of formula (14), or apharmaceutically acceptable salt thereof, wherein a compound of formula(13):

or a pharmaceutically acceptable salt thereof, is treated under suitableconditions to form the compound of formula (14), or a pharmaceuticallyacceptable salt thereof.

Of this embodiment, another embodiment is a method which furthercomprises the preparation of the compound of formula (13), or apharmaceutically acceptable salt thereof, wherein a compound of formula(12):

is reacted with a Grignard reagent of formula (3):

under suitable conditions to form an intermediate product; and then theintermediate product is reacted with a compound of formula (1):

or a pharmaceutically acceptable salt thereof, under suitable conditionsto form the compound of formula (13), or a pharmaceutically acceptablesalt thereof.

Of this embodiment, another embodiment is a method which furthercomprises the preparation of the compound of formula (12), or apharmaceutically acceptable salt thereof, wherein a compound of formula(11):

is treated with an oxidizing agent under suitable conditions to form thecompound of formula (12), or a pharmaceutically acceptable salt thereof.

Of this embodiment, another embodiment is a method which furthercomprises the preparation of the compound of formula (11), wherein acompound of formula (10):

is treated with a suitable alkylating reagent under suitable conditionsto form the compound of formula (11).Specific embodiments of the methods of the invention, including thesuitable conditions for each of the above described steps, are describedin more detail below in the Methods of the Invention.

Methods of the Invention

The methods of the invention are directed to methods of preparingcompounds of formulae (I) and (II) and the compounds of formulae (I-S),(I-R), (II-S) and/or (II-R), as described herein, or pharmaceuticallyacceptable salts thereof.

In general, starting components may be obtained from sources such asSigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific,TCI, and Fluorochem USA, etc. or synthesized according to sources knownto those skilled in the art (see, e.g., Smith, M. B. and J. March,Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5thedition (Wiley, December 2000)) or prepared as described herein or bythe methods disclosed in PCT Published Patent Application No. WO2006/110917, PCT Published Patent Application No. WO 2010/45251 and PCTPatent Application No. PCT/US2010/040187.

Preparation of Compounds of Formulae (I), (I-S) and (I-R)

Compounds of formulae (I), (I-S) and (I-R) are prepared as describedbelow in Reaction Scheme 1:

Compounds of formula (1), formula (2), formula (3) and formula (9) arecommercially available, or can be prepared by methods known to one skillin the art.

In general, compounds of formula (I), (I-S) and (I-R) are prepared bythe method disclosed above in Reaction Scheme 1 by first reacting acompound of formula (2) with a suitable Grignard reagent (such as thatof formula (3)) under suitable conditions, such as at a temperature ofbetween about −25° C. and about 25° C., preferably at about 0° C., toallow for the formation of a magnesium halide intermediate product. Thisintermediate product undergoes nucleophilic addition with theketo-carbonyl group of the isatin compound of formula (1) under suitableconditions, such as in a solvent, preferably, but not limited to,tetrahydrofuran or dichloromethane, to afford the oxindole compound offormula (4).

The removal of the hydroxyl group at the C-3 position of the oxindolering in the compound of formula (4) is achieved by treating the compoundof formula (4) under suitable conditions, such as treatment with asilane reagent, such as triethylsilane, in the presence of an acid, suchas, but not limited to, trifluoroacetic acid, to yield the compound offormula (5). The removal of the hydroxyl group can also be achieved bytreating the compound of formula (4) under suitable conditions, such astreatment with SOCl₂/NEt₃, followed by reduction of the resultingintermediate with Zn dust, to give the compound of formula (5).Alternatively, the removal can be achieved by treating the compound offormula (4) with hydriodic acid to give the compound of formula (5).

The compound of formula (5) is then treated under suitable conditions,such as treatment with a base, preferably, but not limited to,diisopropylamine, diisopropylethyl amine, lithium diisopropylamide,lithium hydroxide or sodium hydroxide, followed by reaction withformaldehyde or paraformaldehyde, to yield the hydroxymethylintermediate compound of formula (6).

Intramolecular cyclization of the compound of formula (6) to yield thecompound of formula (7) is achieved by treating the compound of formula(6) to standard Mitsunobu reaction conditions, such as the employment ofa phosphine reagent, preferably, but not limited to, triphenylphosphineor tributylphosphine, and an azo reagent, preferably, but not limitedto, diethyl azodicarboxylate, diisopropyl azodicarboxylate,di-tert-butyl azodicarboxylate or tetramethyl diazenedicarboxamide, in asolvent, preferably, but not limited to, tetrahydrofuran,dichloromethane or ethyl acetate. The resulting compound of formula (7)can be isolated from the reaction mixture by standard isolationtechniques or used directly in the next step without being isolated fromthe reaction mixture.

Alternatively, intramolecular cyclization is achieved by treating thecompound of formula (5) with a suitable bis-electrophile such as, butnot limited to, chloroiodomethane in the presence of a base such as, butnot limited to, cesium carbonate in a suitable solvent such as, but notlimited to, N,N-dimethylformamide or methyl ethyl ketone to provide acompound of formula (8).

The removal of the hydroxymethyl group on the nitrogen of the compoundof formula (7) is achieved by treating the compound of formula (7) witha base, preferably, but not limited to, sodium hydroxide, lithiumhydroxide or ammonium hydroxide, under suitable conditions to provide acompound of formula (8), which can be isolated from the reaction mixtureby standard isolation techniques.

The compound of formula (8) is then reacted with an electrophile offormula (9) under suitable conditions, such as in the presence of abase, preferably, but not limited to, sodium hydride, cesium carbonateor sodium hydroxide, in a solvent, preferably, but not limited to,N,N-dimethylformamide, acetonitrile, tetrahydrofuran or acetone, toyield the compound of formula (I), which can be isolated from thereaction mixture by standard isolation techniques.

The compound of formula (I) can be resolved into the (S)-enantiomer(i.e., the compound of formula (I-S)) and the corresponding(R)-enantiomer (i.e., the compound of formula (I-R)) under suitableconditions, for example, by chiral chromatographic separation such as,but not limited to, simulated moving bed chromatography or chiral HPLC.

Preparation of Compounds of Formulae (II), (II-S) and (II-R)

Compounds of formula (II), (II-S) and (II-R) are prepared as describedbelow in Reaction Scheme 2:

Compounds of formula (10), formula (11), formula (12), formula (1),formula (3) and formula (16) are commercially available, or can beprepared by methods known to one of skill in the art.

In general, compounds of formulae (II), (II-S) and (II-R) are preparedby the method disclosed above in Reaction Scheme 2 by first heating adihydroxyaldehyde of formula (10) with a suitable bis-alkylating reagentsuch as, but not limited to, 1,2-dibromoethane in the presence of a basesuch as, but not limited to, potassium carbonate in a solvent such as,but not limited to, acetone to provide a compound of formula (11).

Compounds of formula (12) are prepared by treatment of a compound offormula (11) with an oxidizing agent such as, but not limited to,3-chloroperoxybenzoic acid in the presence of a base such as, but notlimited to, sodium bicarbonate in a suitable solvent such as, but notlimited to, dichloromethane, followed by treatment with water and a basesuch as, but not limited to, sodium hydroxide to provide a compound offormula (12).

The compound of formula (12) is then treated with a suitable Grignardreagent such as, but not limited to, the Griganrd reagent of formula (3)under suitable conditions, such as at a temperature of between about−25° C. and about 25° C., preferably at about 0° C., to form aphenyloxymagnesium halide intermediate product which is then reactedwith the compound of formula (1) under suitable conditions, such as in apolar non-protic solvent, preferably, but not limited to,dichloromethane or tetrahydrofuran, to afford the oxindole compound offormula (13).

The removal of the hydroxyl group at the C-3 position of the oxindolecompound of formula (13) is achieved by treating the compound of formula(13) under suitable conditions, such as treatment with a silane reagent,preferably, but not limited to, triethylsilane, in the presence of anacid, preferably, but not limited to, trifluoroacetic acid, to producethe compound of formula (14). The removal of the hydroxyl group at C-3position of the oxindole compound of formula (13) can also be achievedby first treating the compound of formula (13) with SOCl₂/NEt₃, thenreducing the resulting intermediate with Zn dust to give the compound offormula (14). Alternatively, the removal can be achieved by treating thecompound of formula (13) with hydriodic acid to give the compound offormula (14).

Intramolecular cyclization is achieved by treating the compound offormula (14) with a bis-alkylating agent, preferably, but not limitedto, chloroiodomethane, under suitable conditions, such as in thepresence of a base, preferably, but not limited to, cesium carbonate, toproduce the compound of formula (15), which is isolated from thereaction mixture by standard isolation techniques.

The compound of formula (15) is then reacted with an electrophile offormula (16) under suitable conditions, such as in the presence of abase, preferably, but not limited to, sodium hydride, cesium carbonateor sodium hydroxide, in a solvent, preferably, but not limited to,N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane oracetone, to yield the compound of formula (II), which can be isolatedfrom the reaction mixture by standard isolation techniques.

The compound of formula (II) may be chromatographically resolved intothe (S)-enantiomer (i.e., the compound of formula (II-S)) and thecorresponding (R)-enantiomer (i.e., the compound of formula (II-R)) bysimulated moving bed chromatography using a suitable chiral stationaryphase such as, but not limited to, ChiralPAK®-IC and a suitable mobilephase such as, but not limited to, dichloromethane/acetone.

All of the compounds described above as being prepared which may existin free base or acid form may be converted to their pharmaceuticallyacceptable salts by treatment with the appropriate inorganic or organicbase or acid. Salts of the compounds prepared above may be converted totheir free base or acid form by standard techniques. It is understoodthat all polymorphs, amorphous forms, anhydrates, hydrates, solvates andsalts of the compounds of formula (I) and (II) are intended to be withinthe scope of the invention. Furthermore, all compounds of formula (I)and (II) which contain an acid or an ester group can be converted to thecorresponding ester or acid, respectively, by methods known to oneskilled in the art or by methods described herein.

The following specific Synthetic Preparations (for the preparation ofstarting materials and intermediates) and Synthetic Examples (for thepreparation of the compounds of formula (I) and formula (II) by themethods of the invention) are provided as a guide to assist in thepractice of the invention, and are not intended as a limitation on thescope of the invention. Where one or more NMR's are given for aparticular compound, each NMR may represent a single stereoisomer, anon-racemic mixture of stereoisomers or a racemic mixture of thestereoisomers of the compound.

Synthetic Preparation 1 Synthesis of3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-oneCompound of Formula (4)

A 630 L reactor was charged with sesamol (42.6 kg, 299 mol).Tetrahydrofuran (400 kg) was added and the resultant solution was cooledto 1° C. over 42 minutes. Isopropylmagnesium chloride (2 M solution intetrahydrofuran, 173 kg, 337 mol) was added over 2 h such that theinternal temperature was kept between 0 and 4° C. Once the addition wascomplete, the internal temperature was lowered to −5° C. and isatin(37.9 kg, 250 mol) was added in four portions. The reaction mixture wasstirred for 2.75 h at 1 to 3° C. A 1000 L reactor was charged withammonium chloride (72 kg), followed by deionized water (356 kg). Themixture was stirred at 15° C. until the solid had completely dissolvedand the resultant solution was cooled to 1° C. over 1 h. The contents ofthe 630 L reactor were transferred to the 1000 L reactor over 1 h suchthat the internal temperature remained between 3 and 4° C. The 630 Lreactor was rinsed with toluene (133 kg) and the rinse solution added tothe 1000 L reactor. The contents of the 1000 L reactor were allowed towarm to 20-25° C. over 29 minutes and were stirred for a further 15minutes. The stirring was stopped and the contents of the reactor heldat 25° C. for 15 minutes, allowing the phases to separate. The aqueousphase was removed and a solution of sodium chloride (42 kg) in deionizedwater (218 kg) was added over 25 minutes at an internal temperature of22-24° C. The stirring was stopped and the mixture held at 25° C. for 1h, allowing the phases to separate. The organic phase was degassed for0.5 h with nitrogen and toluene (89 kg) was added. A 300 mbar vacuum wasapplied to the reactor and the reactors external temperature was set to50-60° C. Volatile components of the mixture were removed bydistillation over a period of 12 h such that 670 L of distillate werecollected. The reactors external temperature was set to 20-25° C. Anorange precipitate was deposited upon cooling. Toluene (114 kg) wasadded and the suspension stirred for 10 minutes. The solid was collectedby filtration, washed with tert-butyl methyl ether (171 kg) and heptane(85 kg) and dried at 55-60° C. under a reduced pressure of 170 to 4 mbarover a period of 10.5 h to afford3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one(73.5 kg, quantitative yield) as a pale pink solid: purity (HPLC-UV at300 nm) 99.3% a/a; ¹H NMR (300 MHz, DMSO-d₆) δ10.18 (s, 1H), 9.08 (s,1H), 7.21-7.07 (m, 2H), 6.88-6.74 (m, 3H), 6.38 (br s, 1H), 6.23 (s,1H), 5.92 (s, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ178.4, 148.4, 146.6,143.0, 139.4, 133.2, 128.6, 123.8, 121.1, 120.1, 109.0, 106.8, 100.8,97.4, 75.1.

Synthetic Preparation 2 Synthesis of3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one Compoundof Formula (5)

A 1600 L reactor was charged with3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one(113.1 kg, 396 mol), evacuated and filled with nitrogen. Trifluoroaceticacid (679 kg) was added in two portions over 20 minutes and the internaltemperature was lowered to 10° C. over 1 h. Triethylsilane (69.2 kg, 595mol) was added over 2 h 05 min at 10-11° C. and the mixture was stirredfor a further 0.5 h at 10-11° C. A 1000 L reactor was charged withheptane (524 kg) and tert-butyl methyl ether (63 kg). The contents ofthe 1000 L reactor were transferred to the 1600 L reactor over 13minutes at an internal temperature of 10-11° C. The resultantyellow-orange suspension was allowed to warm to 23° C. over 1 h. Thesolid was collected by filtration, washed with heptane (464 kg) followedby tert-butyl methyl ether (57 kg) and dried at 50° C. under a reducedpressure of 58 to 7 mbar over a period of 25 h to afford3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (82.8 kg,75%) as an off-white solid: purity (HPLC-UV at 300 nm) 98.0% a/a; ¹H NMR(300 MHz, DMSO-d₆) δ10.40 (s, 1H), 9.25 (s, 1H), 7.17-7.10 (m, 1H),6.95-6.81 (m, 3H), 6.55 (s, 1H), 6.43 (s, 1H), 5.92-5.85 (m, 2H), 4.66(s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ177.9, 150.1, 146.6, 142.7, 139.6,130.9, 127.4, 123.8, 121.2, 115.9, 109.5, 109.0, 100.7, 97.8, 55.0.

Synthetic Preparation 3 Synthesis of3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-bis(hydroxymethyl)-1,3-dihydro-2H-indol-2-oneCompound of Formula (6)

A 1000 L reactor was charged with3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one (56.3 kg,209 mol), followed by paraformaldehyde (25.4 kg, 847 mol) and deionizedwater (285 kg). The reaction mixture was cooled to an internaltemperature of 5° C. over 25 minutes and a 30% by weight aqueoussolution of sodium hydroxide (113 kg, 847 mol) was added at 5° C. over40 minutes. The reaction mixture was stirred for 1 h at 5° C. A second1000 L reactor was charged with deionized water (260 kg) and 32%hydrochloric acid (124 kg). The contents of the first reactor were addedto the contents of the second reactor at 1° C. over 80 minutes. Thefirst reactor was rinsed with deionized water (35 kg) and the rinsesolution transferred to the second reactor. The resultant suspension wasstirred for at 1° C. for 1 h and the solid was collected by filtration,washed with a mixture of concentrated hydrochloric acid (11 kg) andwater (20 kg) and dried at 55-60° C. under a reduced pressure of 50 to 6mbar over a period of 24 h to afford3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-bis(hydroxymethyl)-1,3-dihydro-2H-indol-2-one(69.8 kg, 99%) as a pale brown solid: purity (HPLC-UV at 230 nm) 95.4%a/a; ¹H NMR (DMSO-d₆, 300 MHz) δ9.06 (s, 1H), 7.17-6.84 (m, 5H),6.19-6.10 (m, 2H), 5.86 (s, 2H), 5.12-4.92 (m, 3H), 4.11-4.06 (m, 1H),3.79-3.73 (m, 1H); ¹³C NMR (DMSO-d₆, 75 MHz) δ179.0, 150.5, 146.7,143.9, 139.9, 132.6, 127.4, 124.0, 121.9, 118.2, 108.7, 108.6, 101.1,98.0, 65.4, 63.2, 56.2.

Synthetic Preparation 4 Synthesis ofspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one Compound ofFormula (8)

A 1000 L reactor was charged with3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-bis(hydroxymethyl)-1,3-dihydro-2H-indol-2-one(65.0 kg, 197 mol), followed by tetrahydrofuran (586 kg). The resultantsolution was cooled to −4° C. over 20 minutes and tri-n-butylphosphine(40.0 kg, 197 mol) was added over 6 minutes, followed by a solution ofdiisopropyl azodicarboxylate (44.8 kg, 197 mol) in tetrahydrofuran (75kg) over 125 minutes such that the internal temperature remained below0° C. The reaction mixture was stirred at −3° C. for a further 25minutes and the contents of the reactor were transferred to a 2500 Lreactor. The 1000 L reactor was rinsed with tetrahydrofuran (16 kg) andthe rinse solution added to the 2500 L reactor. A 25% by weight solutionof ammonia in water (118 kg) was added at −3 to −2° C. over 30 minutes.The reaction mixture was allowed to warm to 25° C. over 1.25 h and wasstirred for a further 2 h. Deionized water (650 kg) and ethyl acetate(585 kg) were added and the mixture was warmed to 40° C. over 40minutes. After stirring for a further 15 minutes, the stirring wasstopped and the phases were allowed to separate for 1 h. The aqueousphase was removed and deionized water (650 kg) was added. The mixturewas stirred for 15 minutes at 40° C. The stirring was stopped and thephases were allowed to separate for 1 h. The aqueous phase was removedand deionized water (325 kg) was added. The mixture was partiallyconcentrated by distillation under reduced pressure at an internaltemperature of 21-39° C. and a pressure of 382 to 98 mbar until 950 L ofdistillate had been collected over a period of 4.5 h. Methanol (1600 kg)was added and the mixture heated to 60° C. over 35 minutes. The mixturewas partially concentrated by distillation under reduced pressure at aninternal temperature of 32-58° C. and a pressure of 530 to 170 mbaruntil 1260 L of distillate had been collected over a period of 9.33 h.The resultant suspension was allowed to cool to 22° C. over 2 h and wasstirred for a further 6 h. The solid was collected by filtration, washedwith a mixture of methanol (34 kg) and deionized water (17 kg) and driedat 55-60° C. under a reduced pressure of 50 to 3 mbar over a period of31 h to afford 35.8 kg of a brown solid, which was transferred to a 400L reactor. Methanol (163 kg) was added and the resultant suspension wasstirred for 0.5 h. The mixture was heated to reflux over a period of 35minutes and was heated at reflux for a further 15 minutes. Deionizedwater (33 kg) was added and the mixture was heated at reflux for 155minutes. The suspension was filtered while hot and the filter cake waswashed with a mixture of methanol (22 kg) and deionized water (11 kg)and dried at 55-60° C. under a reduced pressure of 50 to 4 mbar over aperiod of 8 h to affordspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]2′(1H)-one (30.44 kg, 49%)as a pale brown solid: purity (HPLC-UV at 230 nm) 89.4%; MS (ES+) m/z282.3 (M+1); ¹H NMR (400 MHz, CDCl₃) δ10.56 (s, 1H), 7.27-6.92 (m, 4H),6.67 (s, 1H), 6.26 (s, 1H), 5.93 (s, 2H), 4.79-4.64 (m, 2H).

Synthetic Preparation 5 Synthesis of2,3-dihydro-1,4-benzodioxine-6-carbaldehyde Compound of Formula (11)

A 2000 L reactor was charged with acetone (404.5 kg), followed bypotassium carbonate (256 kg, 1852 mol) and 1,2-dibromoethane (241.5 kg,1298 mol). The mixture was heated at reflux. A 500 L reactor was chargedwith acetone (606 kg) and 3,4-dihydroxybenzalhdehyde (128 kg, 926 mol).The contents of the 500 L reactor were added to the 2000 L reactor at arate of 150-180 kg/h while the reaction temperature was maintained at50-60° C. The reaction mixture was stirred at 54-60° C. for 12 h, wascooled to 20° C. and was filtered through a 500 L Nutsche filter. Thefilter cake was washed with acetone (2×202 kg). The filtrate and acetonewashes were combined in a 2000 L reactor and the resultant solution wasconcentrated to dryness under reduced pressure at a temperature <40° C.To the residue was added ethyl acetate (683 kg) and the resultantsolution was washed with a 5% by weight aqueous solution of potassiumcarbonate (256 kg). The mixture was stirred for 0.5 h, allowed to settlefor 0.5 h and the aqueous phase was removed. This washing procedure wasrepeated three times in total. The organic phase was temporarily setaside into drums. A 2000 L reactor was charged with the combined aqueouswashes, followed by ethyl acetate (113.9 kg). The mixture was stirredfor 0.5 h, allowed to settle for 0.5 h and the aqueous phase wasremoved. The organic phase from the drums was added to the reactorfollowed by a 28% by weight aqueous solution of sodium chloride (192kg). The mixture was stirred for 0.5 h, allowed to settle for 0.5 h andthe aqueous phase was removed. The organic phase was concentrated underreduced pressure at a temperature <45° C. until the mixture's ethylacetate content was below 10% (as determined by gas chromatography).Petroleum ether (268.8 kg) was added to the residue at a rate of 80-90kg/h while the mixture was maintained at a temperature of 35-45° C. Themixture was cooled to 5° C. over 3 h and held at this temperature for afurther 1 h, during which time a precipitate was deposited. Theresultant slurry was filtered through a centrifugal filter and dried toafford 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (111.4 kg, 73%) as anoff-white solid: purity (HPLC-UV at 230 nm) 99.3%.

Synthetic Preparation 6 Synthesis of 2,3-dihydro-1,4-benzodioxin-6-olCompound of Formula (12)

A 2000 L reactor was charged with dichloromethane (1303.4 kg) followedby 2,3-dihydro-1,4-benzodioxine-6-carbaldehyde (98.0 kg, 597 mol) andstirred until a homogeneous solution was obtained. 3-Chloroperoxybenzoicacid (144.3 kg, 836 mol) was added. The mixture was heated to reflux ata rate of 8-10° C./h, heated at reflux for a further 6 h and allowed tocool to 20° C. The resultant suspension was filtered through a 500 LNutsche filter and the filter cake was washed with dichloromethane (391kg). The filtrate and wash solution were transferred to a 2000 Lreactor. A 7% by weight aqueous solution of sodium bicarbonate (212.7kg) was added and the mixture was stirred for 0.5 h. The stirring wasstopped and the phases were allowed to separate over 0.5 h. The aqueouslayer was removed. The aqueous sodium bicarbonate washing procedure wasrepeated three times in total. The organic phase was concentrated todryness under reduced pressure at a temperature <30° C. Methanol (116.1kg) was added and the resultant mixture was cooled to 0° C. A 15.5% byweight aqueous solution of sodium hydroxide (234.3 kg) was added at arate of 30-40 kg/h such that the mixture's temperature was maintainedbetween 0-10° C. The mixture was stirred at this temperature for afurther 2.25 h and the pH of the mixture was adjusted to 6-7 by theaddition of 4 N hydrochloric acid (266.5 kg) such that the mixture'stemperature was maintained between 0-10° C. The mixture was allowed towarm to ambient temperature and was extracted three times in total withmethyl tert-butyl ether (145 kg for each extraction) by stirring for 0.5h, stopping the stirring and allowing the phases to separate for 0.5 h.The combined organic extracts were washed three times in total with a 7%aqueous solution of sodium bicarbonate (212.7 kg for each wash) bystirring for 0.5 h, stopping the stirring, allowing the phases toseparate for 0.5 h and removing the aqueous phase. The organic phase wasthen washed with a 30% by weight aqueous solution of sodium chloride(212.7 kg) by stirring for 0.5 h, stopping the stirring, allowing thephases to separate for 0.5 h and removing the aqueous phase. The organicphase was concentrated to dryness under reduced pressure at atemperature <45° C. Tetrahydrofuran (170 kg) was added and the resultantsolution concentrated to dryness under reduced pressure at a temperature<45° C. Further tetrahydrofuran (17.1 kg) was added and the resultantsolution concentrated to dryness under reduced pressure at a temperature<45° C. Tetrahydrofuran (122.5 kg) was added to afford a brown-redsolution of 2,3-dihydro-1,4-benzodioxin-6-ol (86.3 kg, 95%) intetrahydrofuran which was carried forward without further purification:purity (HPLC-UV at 220 nm) 95.7%.

Synthetic Preparation 7 Synthesis of3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneCompound of Formula (13)

A 1000 L reactor was charged with tetrahydrofuran (296.8 kg). Thetetrahydrofuran was heated at reflux for 1 h and allowed to cool toambient temperature. Magnesium (15.0 kg, 625 mol), iodine (19.5 g,catalytic amount) and bromoethane (147.0 g, catalytic amount) were addedat a temperature of 15-30° C. The resultant mixture was heated at 50-55°C. for 0.5 h and 2-chloropropane (4.5 kg, 57 mol) was added, followed bya 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (7.6kg, catalytic amount). 2-Chloropropane (39.2 kg, 500 mol) was added at arate of 8-10 kg/h such that the temperature of the reaction mixture wasmaintained between 55-70° C. The reaction mixture was heated at 58-68°C. for 3 h, allowed to cool to ambient temperature and was stirred for afurther 4 h. A 2000 L reactor was charged with a solution of2,3-dihydro-1,4-benzodioxin-6-ol (86.3 kg, 567 mol) in tetrahydrofuran(122.5 kg), followed by further tetrahydrofuran (804.1 kg). Theresultant solution was cooled to 0° C. and the contents of the 1000 Lreactor were added to the 2000 L reactor at a rate of 30-50 kg/h suchthat the temperature of the reaction mixture was maintained between 0-5°C. The 1000 L reactor was rinsed three times with tetrahydrofuran (5 kgfor each rinse) and the rinse solutions were added to the 2000 Lreactor. The reaction mixture was stirred at 7-13° C. for 1 h and wascooled to −5° C. Isatin (69.5 kg, 472.5 mol) was added in three equalportions over 0.5 h and the mixture stirred for 0.5 h at −5-0° C. Thereaction mixture was heated at 50-55° C. for 7.5 h and was allowed tocool to ambient temperature. A 5000 L reactor was charged with water(576.9 kg) and ammonium chloride (118.2 kg). The resultant solution wascooled to 0-5° C. The contents of the 2000 L reactor were added to the5000 L reactor at a rate of 300-500 kg/h such that the temperature ofthe mixture was maintained between 0-5° C. The mixture was stirred at15-25° C. for 0.5 h and the stirring was stopped. The phases wereallowed to separate for 1 h and the aqueous phase was removed. A 27% byweight aqueous solution of sodium chloride (69.6 kg) was added and themixture stirred for 0.5 h. The stirring was stopped, the phases wereallowed to separate for 1 h and the aqueous layer was removed. Theaqueous sodium chloride wash procedure was repeated two times in total.The organic phase was transferred to a 2000 L reactor and wasconcentrated under reduced pressure at a temperature of 45-55° C.Toluene (302.3 kg) was added to the residue at a rate of 90-130 kg/h andat a temperature of 45-50° C. The resultant mixture was cooled to 15° C.at a rate of 8-10° C./h and stirred for at 10-15° C. for a further 1 h.The resultant slurry was filtered through a centrifugal filter and thefilter cake was washed with water (69.5 kg) and dried at 45-50° C. toafford3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one(130.8 kg, 93%) as an off-white solid: purity (HPLC-UV at 210 nm) 99.7%.

Synthetic Preparation 8 Synthesis of3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-oneCompound of Formula (14)

A 2000 L reactor was charged with dichloromethane (489.4 kg), followedby3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one(92.0 kg, 307 mol) in four 23 kg portions over 1 h. The resultantsolution was stirred at ambient temperature for 1 h and triethylsilane(107.2 kg, 921 mol) was added. The mixture was cooled to −5° C. andtrifluoroacetic acid (105.1 kg, 921 mol) was added at a rate of 25-30kg/h such that the temperature of the reaction mixture remained below 0°C. The mixture was stirred at −5-0° C. for 2.5 h, warmed to 18-20° C.,stirred for a further 6.5 h and concentrated to dryness under reducedpressure at a temperature <30° C. Methyl tert-butyl ether (139.8 kg) wasadded to the residue at 15-20° C. and the mixture concentrated tonear-dryness under reduced pressure at a temperature <35° C. The mixturewas filtered in a centrifugal filter and a 2000 L reactor was chargedwith the filter cake, followed by methanol (72.7 kg). The mixture wasstirred at 10-15° C. for 0.5 h and filtered in a centrifugal filter. Thefilter cake was dried under reduced pressure at 40-50° C. to afford3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one(68.0 kg, 78%) as a colorless solid: purity (HPLC-UV at 254 nm) 99.3%.

Synthetic Preparation 9 Synthesis of2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneCompound of Formula (15)

A 2000 L stainless steel crystallizer was charged withN,N-dimethylformamide (113.7 kg) and tetrahydrofuran (1070.9 kg). Thecontents were cooled to 0-5° C. and3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one(12.0 kg, 42.4 mol) was added, followed by cesium carbonate (30.4 kg,93.3 mol). A solution of chloroiodomethane (9.4 kg, 53.7 mol) inN,N-dimethylformamide (16.9 kg) was added at a rate of 39.5 kg/h suchthat the temperature of the reaction mixture was maintained between 0and 5° C. The reaction mixture was stirred at 0-5° C. for 2 h and heatedat 20-25° C. for 18.5 h. The mixture was filtered and the filter cakewas suspended in tetrahydrofuran (26.4 kg) and filtered again. Thecombined filtrates were combined and concentrated to a volume of 110 Lunder reduced pressure at a temperature <60° C. The mixture was cooledto 20-25° C. and purified water (1200.8 kg) was added at a rate of 343.1kg/h. The mixture was cooled to 0-5° C. and filtered. The filter cakewas suspended in water (310.5 kg), filtered and dried at a temperature<60° C. until the water content was 10.6% by weight by Karl-Fishertitration. A 200 L reactor was charged with tetrahydrofuran (98.0 kg).The partially-dried filter cake (˜11.0 kg) was added to the 200 Lreactor by means of a solid addition funnel. The mixture was heated atreflux for 4.5 h, cooled to 10-15° C. and stirred for 3.5 h at 10-15° C.The mixture was filtered and the filter cake was washed with cold (0-5°C.) tetrahydrofuran (2×10.7 kg) and dried in a tray dryer at atemperature <55° C. to afford2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(6.88 kg, 63%) as a pale yellow solid: purity (HPLC-UV at 210 nm) 98.3%;mp >250° C.; ¹H NMR (300 MHz, DMSO-d₆) δ10.58 (br s, 1H), 7.26-7.19 (m,1H), 7.09 (d, J=7.2 Hz, 1H), 6.99-6.90 (m, 2H), 6.47 (s, 1H), 6.16 (s,1H), 4.74, 4.60 (ABq, J_(AB)=9.2 Hz, 2H), 4.20-4.07 (m, 4H); ¹³C NMR (75MHz, DMSO-d₆) δ178.4, 154.7, 144.0, 141.8, 137.8, 132.6, 128.7, 123.8,122.3, 121.5, 111.1, 109.8, 98.7, 79.5, 64.2, 63.6, 57.7; MS (ES+) m/z295.9 (M+1).

Synthetic Example 1 Synthesis of1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-oneCompound of Formula (I)

A 100 L reactor was charged withspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (6.03 kg,19.5 mol), followed by cesium carbonate (16.02 kg, 48.7 mol). Acetone(48.8 kg) was added and the resultant suspension was heated to refluxover 1 h. 2-Bromomethyl-5-(trifluoromethyl)furan (4.92 kg, 21.2 mol) wasadded by means of an addition funnel over a period of 2 h while thereaction mixture was maintained at reflux. The reaction mixture wasstirred at reflux for a further 2 h and the acetone was removed bydistillation at atmospheric pressure until 37 L of distillate had beencollected. Toluene (48.8 kg) was added and the distillation wascontinued, first at atmospheric pressure then under reduced pressureuntil 37 L of distillate had been collected. Toluene (36.9 kg) was addedand the distillation was continued at 54-55° C. and a pressure of150-180 mbar until 37 L of distillate had been collected. The contentsof the 100 L reactor were allowed to cool to 25° C. and toluene (40.9kg) was added. The contents of the 100 L reactor were transferred to a200 L reactor and deionized water (48.8 kg) was added. The stirredmixture was warmed to 39° C., the stirring was stopped and the phaseswere allowed to separate for 11 h. The lower phase was removed and theremaining toluene phase was subjected to distillation at 55-64° C. undera reduced pressure of 100 mbar until 18 L of distillate had beencollected. The resultant solution was diluted with toluene to a totalvolume of 98 L. The contents of the 200 L reactor were passed through achromatography column packed with silica gel (20 kg) and toluene (40kg). The column was eluted with toluene such that ten 30 kg fractionswere collected. The column was washed with acetone (100 kg). Fractions 2through 10 were successively transferred to a 200 L reactor as adistillation under reduced pressure was proceeding. The contents of thereactor were adjusted with toluene to a volume of 50 L and the solutionwas heated to 79° C. Heptane (85 kg) was added over 15 minutes and themixture was cooled to 10° C. over a period of 3 h. Crystallizationstarted at an internal temperature of 56° C. The solid was collected byfiltration, washed with a mixture of heptane (10.2 kg) and toluene (5.1kg) and dried at 45-50° C. under a reduced pressure of 50 mbar over aperiod of 15 h to afford1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one(6.08 kg, 73%) as a colorless solid: purity (HPLC-UV at 230 nm) 99.6%;mp 139-141° C.; ¹H NMR (300 MHz, CDCl₃) δ7.32-6.97 (m, 5H), 6.72 (d,J=3.3 Hz, 1H), 6.66 (s, 1H), 6.07 (s, 1H), 5.90-5.88 (m, 2H), 5.05, 4.86(ABq, J_(AB)=16.1 Hz, 2H), 4.91 (d, J=9.0 Hz, 1H), 4.66 (d, J=9.0 Hz,1H); ¹³C NMR (75 MHz, CDCl₃) δ176.9, 155.7, 153.5, 148.8, 142.2, 141.9,140.8, 140.2, 139.7, 139.1, 132.1, 129.2, 124.7, 124.1, 123.7, 121.1,120.1, 117.6, 114.5, 114.4, 110.3, 109.7, 103.0, 101.9, 93.8, 80.0,57.8, 36.9; MS (ES+) m/z 430.2 (M+1), 452.2 (M+23); Calc'd forC₂₂H₁₄F₃NO₅: C, 61.54%; H, 3.29%; N, 3.26%; Found: C, 61.51%; H, 3.29%;N, 3.26%.

Synthetic Example 2 Resolution of Compound of Formula (I) by Chiral HPLC

The compound of formula (I) was resolved into the compound of formula(I-S) and the compound of formula (I-R) by chiral HPLC under thefollowing conditions:

-   -   Column: Chiralcel® OJ-RH; 20 mm I.D.×250 mm, 5 mic; Lot: OJRH        CJ-EH001 (Daicel Chemical Industries, Ltd)    -   Eluent: Acetonitrile/Water (60/40, v/v, isocratic)    -   Flow rate: 10 mL/min    -   Run time: 60 min    -   Loading: 100 mg of compound of formula (I) in 1 mL of        acetonitrile    -   Temperature: Ambient

Under the above chiral HPLC conditions, the compound of formula (I-R),i.e.,(R)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro[furo[2,3-f][1,3]-benzodioxole-7,3′-indol]-2′(1′H)-one,was isolated as the first fraction as a white solid; ee (enantiomericexcess) >99% (analytical OJ-RH, 55% acetonitrile in water); mp 103-105°C.; ¹H NMR (300 MHz, DMSO-d₆) δ7.32-6.99 (m, 5H), 6.71 (d, J=3.4 Hz,1H), 6.67 (s, 1H), 6.05 (s, 1H), 5.89 (d, J=6.2 Hz, 2H), 5.13, 5.02(ABq, J_(AB)=16.4 Hz, 2H), 4.82, 4.72 (ABq, J_(AB)=9.4 Hz, 2H); ¹³C NMR(75 MHz, CDCl₃) δ177.2, 155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0,129.1, 123.9, 120.6, 119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6,93.5, 80.3, 58.2, 36.9; MS (ES+) m/z 430.2 (M+1), [α]_(D) −17.46° (c0.99, DMSO). The compound of formula (I-S), i.e.,(S)-1′-{[5-(trifluoromethyl)furan-2-yl]methyl}spiro-[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one,was isolated as the second fraction as a white solid; ee>99% (analyticalOJ-RH, 55% acetonitrile in water); mp 100-102° C.; ¹H NMR (300 MHz,DMSO-d₆) δ7.32-6.99 (m, 5H), 6.71 (d, J=3.4 Hz, 1H), 6.67 (s, 1H), 6.05(s, 1H), 5.89 (d, J=6.3 Hz, 2H), 5.12, 5.02 (ABq, J_(AB)=16.4 Hz, 2H),4.82, 4.72 (ABq, J_(AB)=9.4 Hz, 2H); ¹³C NMR (75 MHz, CDCl₃) δ177.2,155.9, 152.0, 149.0, 142.4, 142.0, 141.3, 132.0, 129.1, 123.9, 120.6,119.2, 117.0, 112.6, 109.3, 108.9, 103.0, 101.6, 93.5, 80.3, 58.2, 36.9;MS (ES+) m/z 430.2 (M+1), [α]_(D)+14.04° (c 0.99, DMSO).

Synthetic Example 3 Resolution of Compound of Formula (I) by SMBChromatography

The compound of formula (I) was resolved into the compound of formula(I-S) and the compound of formula (I-R) by SMB chromatography under thefollowing conditions:

-   -   Extract: 147.05 mL/min    -   Raffinate: 86.13 mL/min    -   Eluent: 183.18 mL/min    -   Feed: 50 mL/min    -   Recycling: 407.88 mL/min    -   Run Time: 0.57 min    -   Temperature: 25° C.    -   Pressure: 55 bar

The feed solution (25 g of compound of formula (I) in 1.0 L of mobilephase (25:75 (v:v) mixture of acetonitrile/methanol)) was injectedcontinuously into the SMB system (Novasep Licosep Lab Unit), which wasequipped with eight identical columns in 2-2-2-2 configurationcontaining 110 g (per column, 9.6 cm, 4.8 cm I.D.) of ChiralPAK-AD asstationary phase. The first eluting enantiomer (the compound of formula(I-R)) was contained in the raffinate stream and the second elutingenantiomer (the compound of formula (I-S)) was contained in the extractstream. The characterization data of the compound of formula (I-R) andthe compound of formula (I-S) obtained from the SMB resolution wereidentical to those obtained above utilizing chiral HPLC.

The compound of formula (I) was resolved into the compound of formula(I-R) and the compound of formula (I-S) on a Waters preparative LCMSautopurification system. The first-eluting enantiomer from the chiralcolumn was brominated (at a site well-removed from the stereogeniccentre) to give the corresponding 5′-bromo derivative, which wassubsequently crystallized to generate a single crystal suitable forX-ray crystallography. The crystal structure of this brominatedderivative of the first-eluting enantiomer was obtained and its absoluteconfiguration was found to be the same as the compound of formula (1-R).Hence, the second-eluting enantiomer from the chiral column is thecompound of formula (1-S). Moreover, the material obtained from theextract stream of the SMB resolution had a specific optical rotation ofthe same sign (positive, i.e. dextrorotatory) as that of the materialobtained from the aforementioned LC resolution.

Synthetic Example 4 Synthesis of1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-oneCompound of Formula (II)

A 160 L reactor was charged with 1,4-dioxane (43 L) at ambienttemperature followed by2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(6.80 kg, 23 mol). To the resultant suspension was added cesiumcarbonate (18.7 kg, 58 mol) and the mixture was heated to 82° C. over 72minutes. A container was rinsed with 1,4-diozane (7 L) and used for theaddition of 2-(Chloromethyl)-3-(trifluoromethyl)pyridine hydrochloride(5.88 kg, 25 mol) portionwise over 35 minutes. The temperature of thereaction mixture was increased to 100° C. over 43 minutes and themixture stirred at 100° C. for 3 h, cooled to 20° C. over 90 minutes andstirred for a further 16 h. Deionized water (40 L) and dichloromethane(40 L) were added and the resultant mixture stirred at 22° C. for 12minutes. The stirring was stopped and the phases were allowed toseparate for 21 minutes. The aqueous and organic phases were separatedinto drums. A 160 L reactor was charged with the aqueous phase anddichloromethane (41 L) was added. The mixture was stirred at 19° C. for10 minutes, the stirring was stopped and the phases were allowed toseparate for 10 minutes. The aqueous phase was removed and the organicphase from the previous step was transferred from the drum to thereactor. Deionized water (40 L) was added and the mixture stirred at 22°C. for 10 minutes. The stirring was stopped and the phases were allowedto separate for 43 minutes. The aqueous phase was removed and theorganic phase concentrated to dryness under a reduced pressure of 712-97mbar at 19-38° C. To the residue was added methanol (56 L) over 19minutes. The resultant suspension was cooled to 3° C. over 64 minutesand stirred for 98 minutes. The mixture was filtered and the filter cakewashed with cold (0° C.) methanol (14 L) and dried under a reducedpressure of 90-9 mbar at 21-46° C. for 10.5 h to obtain1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(8.00 kg, 81%) as an off-white solid: purity (HPLC-UV) 99.8%; ¹H NMR(300 MHz, CDCl₃) δ8.67-8.63 (m, 1H), 8.01-7.96 (m, 1H), 7.35-7.28 (m,1H), 7.22-7.13 (m, 2H), 7.05-6.98 (m, 1H), 6.63 (s, 1H), 6.62-6.58 (m,1H), 6.49 (s, 1H), 5.42, 5.14 (ABq, J_(AB)=17.3 Hz, 2H), 5.00, 4.74(ABq, J_(AB)=8.9 Hz, 2H), 4.22-4.10 (m, 4H); ¹³C NMR (75 MHz, CDCl₃)δ178.3, 155.3, 152.5, 144.6, 142.4, 138.4, 134.3 (q, ³J_(C-F)=5.2 Hz),132.8, 128.7, 124.4, (q, ²J_(C-F)=32.6 Hz), 123.9 (q, ¹J_(C-F)=273.3Hz), 123.8, 123.4, 122.2, 121.7, 112.6, 108.6, 99.2, 80.2, 64.6, 64.0,58.3, 42.3 (q, ⁴J_(C-F)=3.3 Hz); MS (ES+) m/z 454.8 (M+1).

Synthetic Example 5 Resolution of Compound of Formula (II) by SMBChromatography

The compound of formula (II) was resolved into the compound of formula(II-S) and the compound of formula (II-R) by SMB chromatography underthe following conditions:

-   -   Extract: 182.67 mL/min    -   Raffinate: 67.44 mL/min    -   Eluent: 224.11 mL/min    -   Feed: 26.0 mL/min    -   Recycling: 420 mL/min    -   Run Time: 1.05 min    -   Temperature: 25° C.    -   Pressure: 50-55 bar

The feed solution (68.4 g of compound of formula (II) in 1.0 L of mobilephase (97:3 (v:v) mixture of dichloromethane/acetone)) was injectedcontinuously into the SMB system (Novasep Licosep Lab Unit), which wasequipped with eight identical columns in 2-2-2-2 configurationcontaining 110 g (per column, 10.0 cm, 4.8 cm I.D.) of ChiralPAK®-IC asstationary phase. The compound of formula (II-R) was contained in theraffinate stream and the compound of formula (I-S) was contained in theextract stream.

A total of 10.62 kg of the compound of formula (II) were processed bySMB chromatography using the above conditions. All extract fractionswith a chiral purity (HPLC)>99.0 a/a were pooled, concentrated to avolume of 26 L under reduced pressure and transferred to a 100 Lreactor. The solution was further concentrated under a reduced pressureof 700-590 mbar at 26-37° C. until 13 L of distillate had beencollected. Methanol (25 L) was added and the mixture concentrated undera reduced pressure of 650-360 mbar at 30-38° C. until 15 L of distillatehad been collected. The mixture was cooled to 20° C. and methanol (15 L)was added. The mixture was concentrated under a reduced pressure of650-320 mbar at 20-39° C. until 15 L of distillate had been collectedand was cooled to 1° C. over 53 minutes and stirred for a further 70minutes. The suspension was filtered and the filter cake was washed withcold (0° C.) methanol (9 L) and dried at ambient temperature under aflow of nitrogen gas for 15.5 h. The solid was further dried at areduced pressure of 40-1 mbar at 50° C. for 195 minutes to afford thecompound of formula (II-S), i.e.,(S)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one(3.62 kg) as a colorless solid: purity (HPLC-UV) 100%; ¹H NMR (300 MHz,CDCl₃) δ8.67-8.63 (m, 1H), 8.01-7.96 (m, 1H), 7.35-7.28 (m, 1H),7.22-7.13 (m, 2H), 7.05-6.98 (m, 1H), 6.63 (s, 1H), 6.62-6.58 (m, 1H),6.49 (s, 1H), 5.42, 5.14 (ABq, J_(AB)=17.3 Hz, 2H), 5.00, 4.74 (ABq,J_(AB)=8.9 Hz, 2H), 4.22-4.10 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ178.3,155.3, 152.5, 144.6, 142.4, 138.4, 134.3 (q, ³J_(C-F)=5.2 Hz), 132.8,128.7, 124.4, (q, ²J_(C-F)=32.6 Hz), 123.9 (q, ¹J_(C-F)=273.3 Hz),123.8, 123.4, 122.2, 121.7, 112.6, 108.6, 99.2, 80.2, 64.6, 64.0, 58.3,42.3 (q, ⁴J_(C-F)=3.3 Hz); MS (ES+) m/z 454.8 (M+1); [α]_(D)+45.1° (c2.02, DMSO); ee (CHIRALPAK IC, dichloromethane/acetone 97/3 (v/v)) 100%.

The compound of formula (II-R), i.e.,(R)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one,was isolated from the raffinate by standard procedures.

BIOLOGICAL ASSAYS

In order that the invention described herein may be more fullyunderstood, the following biological assay is set forth to demonstratethe utility of the compounds prepared herein. It should be understoodthat this example is for illustrative purposes only and is not to beconstrued as limiting this invention in any manner.

Biological Example 1 Guanidine Influx Assay (In Vitro Assay)

This example describes an in vitro assay for testing and profiling testagents against human or rat voltage-gated sodium channels stablyexpressed in cells of either an endogenous or heterologously expressedorigin. The assay is also useful for determining the IC₅₀ of avoltage-gated sodium channel modulating (preferably blocking) compound.The assay is based on the guanidine influx assay described by Reddy, N.L., et al., J. Med. Chem. (1998), 41(17):3298-302.

The guanidine influx assay is a radiotracer flux assay used to determineion flux activity of voltage-gated sodium channels in a high-throughputmicroplate-based format. The assay uses ¹⁴C-guanidine hydrochloride incombination with various known voltage-gated sodium channel modulatorsthat produce maintained influx, to assay the potency of test agents.Potency is determined by an IC₅₀ calculation. Selectivity is determinedby comparing potency of the compound for the voltage-gated sodiumchannel of interest to its potency against other voltage-gated sodiumchannels (also called ‘selectivity profiling’).

Each of the test agents is assayed against cells that express thevoltage-gated sodium channels of interest. Voltage-gated sodium channelsare characterized as TTX sensitive or insensitive. This property isuseful when evaluating the activities of a voltage-gated sodium channelof interest when it resides in a mixed population with othervoltage-gated sodium channels. The following Table 1 summarizes celllines useful in screening for a certain voltage-gated sodium channelactivity in the presence or absence of TTX.

TABLE 1 CELL LINE mRNA Expression Functional Characterization CHO-K1(Chinese Na_(v)1.4 expression has been The 18- to 20-fold increase inHamster Ovary; shown by RT-PCR [¹⁴C] guanidine influx was recommended Noother Na_(V) expression has completely blocked using TTX. host cellline) been detected (Na_(V)1.4 is a TTX sensitive ATTC accessionchannel) number CCL-61 L6 (rat myoblast Expression of Na_(v)1.4 and 1.5The 10- to 15-fold increase in cell) ATTC [¹⁴C] guanidine influx wasonly Number CRL-1458 partially blocked by TTX at 100 nM (Na_(v)1.5 isTTX resistant) SH-SY5Y (Human Published Expression of The 10- to 16-foldincrease in neuroblastoma) Na_(V)1.9 and Na_(V)1.7 (Blum et [¹⁴C]guanidine influx above ATTC Number al.) background was partially blockedCRL-2266 by TTX (Na_(V)1.9 is TTX resistant) SK-N-BE2C (a Expression ofNa_(V)1.8 Stimulation of BE2C cells with human pyrethroids results in a6-fold neuroblastoma cell increase in [¹⁴C] guanidine influx line ATCCNumber above background. CRL-2268) TTX partially blocked influx(Na_(V)1.8 is TTX resistant) PC12 (rat Expression of Na_(v)1.2 and The8- to 12-fold increase in [¹⁴C] pheochromocytom Na_(V)1.7 guanidineinflux was completely a) ATTC Number blocked using TTX. (Na_(v)1.2 andCRL-1721 Na_(V)1.7 are TTX sensitive channels) HEK293 (human Expressionof hNa_(V)1.7 Na_(V)1.7 is a TTX sensitive embryonic kidney) channel.The TTX IC₅₀ in the ATTC Number functional Guanidinium assay is CRL-15738 nM.

It is also possible to employ immortalized cell lines thatheterologously express voltage-gated sodium channels. Cloning, stabletransfection and propagation of such cell lines are known to thoseskilled in the art (see, for example, Klugbauer, N, et al., EMBO J.(1995), 14(6):1084-90; and Lossin, C., et al., Neuron (2002), 34, pp.877-884).

Cells expressing the voltage-gated sodium channel of interest are grownaccording to the supplier or in the case of a recombinant cell in thepresence of selective growth media such as G418 (Gibco/Invitrogen). Thecells are disassociated from the culture dishes with an enzymaticsolution (1×) Trypsin/EDTA (Gibco/Invitrogen) and analyzed for densityand viability using haemocytometer (Neubauer). Disassociated cells arewashed and resuspended in their culture media then plated intoPoly-D-Lysine coated Scintiplates (Perkin Elmer) (approximately 100,000cells/well) and incubated at 37° C./5% CO₂ for 20-24 hours. After anextensive wash with Low sodium HEPES-buffered saline solution (LNHBSS)(150 mM Choline Chloride, 20 nM HEPES (Sigma), 1 mM Calcium Chloride, 5mM Potassium Chloride, 1 mM Magnesium Chloride, 10 mM Glucose) the testagents are diluted with LNHBSS and then added to each well at thedesired concentration. (Varying concentrations of test agent may beused). The activation/radiolabel mixture contains an alkaloid such asveratridine or Aconitine (Sigma) or a pyrethroid such as deltamethrin,venom from the scorpion Leiurus quinquestriatus hebraeus (Sigma) and¹⁴C-guanidine hydrochloride (ARC) to measure flux through thevoltage-gated sodium channels.

After loading the cells with test agent and activation/radiolabelmixture, the Poly-D-Lysine coated Scintiplates are incubated at ambienttemperature. Following the incubation, the Poly-D-Lysine coatedScintplates are extensively washed with LNHBSS supplemented withGuanidine (Sigma). The Poly-D-Lysine coated Scintiplates are dried andthen counted using a Wallac MicroBeta TriLux (Perkin-Elmer LifeSciences). The ability of the test agent to block voltage-gated sodiumchannel activity is determined by comparing the amount of ¹⁴C-guanidinepresent inside the cells expressing the different voltage-gated sodiumchannels. Based on this data, a variety of calculations, as set outelsewhere in this specification, may be used to determine whether a testagent is selective for a particular voltage-gated sodium channel.

The IC₅₀ value of a test agent for a specific voltage-gated sodiumchannel may be determined using the above general method. The IC₅₀ maybe determined using a 3, 8, 10, 12 or 16 point curve in duplicate ortriplicate with a starting concentration of 1, 5 or 10 μM dilutedserially with a final concentration reaching the sub-nanomolar,nanomolar and low micromolar ranges. Typically the mid-pointconcentration of test agent is set at 1 μM, and sequentialconcentrations of half dilutions greater or smaller are applied (e.g.,0.5 μM; 5 μM and 0.25 μM; 10 μM and 0.125 μM; 20 μM etc.). The IC₅₀curve is calculated using the 4 Parameter Logistic Model or SigmoidalDose-Response Model formula (fit=(A+((B−A)/(1+((C/x)^D)))).

The fold selectivity, factor of selectivity or multiple of selectivity,is calculated by dividing the IC₅₀ value of the test voltage-gatedsodium channel by the reference voltage-gated sodium channel, forexample, Na_(v)1.5.

Accordingly, the compounds prepared by the methods disclosed hereindemonstrated voltage-gated sodium channel blocking activity againsthNa_(v)1.7 as set forth below in Table 2:

TABLE 2 IC₅₀ Compound Chemical Name (μM) (I)1′-{[5-(trifluoromethyl)furan-2- 0.007yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one(I-R) (R)-1′-{[5-(trifluoromethyl)furan-2- 4.200yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one(I-S) (S)-1′-{[5-(trifluoromethyl)furan-2- 0.003yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′- indol]-2′(1′H)-one(II) 1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-2,3- 0.015dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′- indol]-2′(1′H)-one(II-S) (S)-1′-{[3-(trifluoromethyl)pyridin-2-yl]methyl}- 0.0052,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine- 8,3′-indol]-2′(1′H)-one

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet are incorporated herein by reference, intheir entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

What is claimed is:
 1. A compound selected from the following formulae:

or a pharmaceutically acceptable salt thereof;

or a pharmaceutically acceptable salt thereof; and

or a pharmaceutically acceptable salt thereof.